The molecular messengers that translate inflammatory signals into the genetic changes that tell muscle stem cells to differentiate have been uncovered by a team of scientists.
At Sanford-Burnham Medical Research Institute (Sanford-Burnham), a team of scientists led by Pier Lorenzo Puri discovered the fundamental mechanisms that could be manipulated to enhance how muscle stem cells regenerate injured or diseased muscles. These findings could lead to new treatments for diseases like muscular dystrophy.
"This study helps us understand how muscle stem cells decipher external signals and elaborate them to turn genes on and off," explained Dr. Puri, who is also an associate faculty member at the Dulbecco Telethon Institute in Rome, Italy
Dr. Puri's findings begin with an inflammatory molecule called tumor necrosis factor (TNF), which initiates a chain reaction of molecular events when it wakes up a protein called p38 alpha MAPK. This protein is known to play a role in many processes, but here Dr. Puri and his colleagues show that TNF tells p38 alpha MAPK to enter the nucleus, where it keeps a damper on the part of the genome that defines the identity of muscle cells. Essentially, p38 alpha MAPK determines whether stem cells loitering in adult muscle tissue keep refreshing the pool of stem cells or differentiate into functioning muscle cells.
This new information on p38 alpha MAPK's role in muscle is important because it gives Dr. Puri's group a target to artificially dial the stem cell population up or down. In this study they used a chemical inhibitor and antibodies directed against TNF to block the p38 alpha MAPK activity specifically in stem cells, thus producing more stem cells. Anti-TNF antibodies provide a potential mechanism to generate more muscle stem cells in muscular dystrophy patients, especially since they are already FDA-approved to treat septic shock and arthritis. The team verified their discoveries in a mouse model of Duchenne muscular dystrophy.
"In muscular dystrophy patients, the pool of stem cells capable of regenerating new muscle becomes exhausted," said Dr. Puri.
"Here we've found a strategy to refresh the pool by modulating p38 alpha MAPK. Since the effect of this treatment is reversible, withdrawing the drug could then force the expanded population of stem cells to repopulate muscle cells."
The study has been published in the journal Cell Stem Cell.